Reviews

The introduction of the tyrosine kinase inhibitor (TKI) imatinib (Gleevec) into clinical practice resulted in a very dramatic prolongation of survival for most, but not all, patients with chronic myeloid leukemia in chronic phase (CML-CP). A leukemia with a median survival of about 5 years was transformed into one for which the survival in many cases promises to be comparable to that of normal persons of similar age. The more recently available TKIs, namely nilotinib (Tasigna) and dasatinib (Sprycel), produce more rapid responses but have not yet shown any overall survival advantage compared with long-term administration of imatinib. They are, however, useful in treating imatinib intolerance or resistance. There are currently two choices for initial treatment of CML-CP: (1) starting all new patients on imatinib and changing to a second-generation TKI in those who fail or who are predicted to fare badly, or (2) starting all new patients on a second-generation TKI. This choice may be based primarily on considerations of cost or possible side effects.

Introduction

The management of patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CML-CP) has changed very fundamentally over the past 10 years. Until 1998 there was little dispute that a new patient should be offered treatment by allogeneic stem cell transplantation (allo-SCT) if he or she was relatively young and had a suitable human leukocyte antigen (HLA)-matched sibling donor. If there were no sibling donors, then efforts were made to identify an HLA-matched family member or an unrelated volunteer from the general public. Patients not eligible for treatment by allo-SCT usually received interferon alfa or hydroxyurea, but the median expectation of life ranged between 3 and 6 years. In the 1990s, Druker, working in conjunction with Ciba-Geigy (now Novartis) in Switzerland, developed the 2-phenylaminopyrimidine derivative tyrosine kinase inhibitor (TKI) imatinib mesylate (Gleevec), now referred to just as imatinib, which specifically targeted the BCR-ABL1 oncoprotein characteristic of CML and selectively killed CML cells in vitro.[1,2] Imatinib was first used in the clinic in 1998, and it soon became clear that this agent produced impressive cytogenetic responses in patients with interferon-resistant CML.[3] This led rapidly to the initiation in 2000 of the International Randomized Study of Interferon vs STI571 (IRIS study), in which 1,106 CML-CP patients from 15 countries were recruited over a 6-month period and randomly assigned to receive either imatinib or interferon + cytarabine in a 1:1 ratio. The early results of this study were reported first in 2003[4] and have been updated at intervals since then.[5,6] They showed that imatinib produced an extremely high cumulative incidence of complete cytogenetic responses, and the patients who experienced a complete response had a mortality at 8 years of 16%. The crossover or drop-out of patients from the interferon/cytarabine arm was so great that the comparison component of the study rapidly became inevaluable, but the long-term survival of patients treated in the imatinib arm was of course substantially better than would have been expected based on treatment with interferon in an earlier era.

In the past decade, the notion of treating CML by targeting the BCR-ABL1 oncoprotein has been developed further. Four new TKIs, namely dasatinib (Sprycel), nilotinib (Tasigna), bosutinib (Bosulif), and ponatinib, have been introduced; all have demonstrable efficacy in treating patients whose leukemia has proved resistant to imatinib. The first three agents, dasatinib, nilotinib, and bosutinib, have been compared prospectively with imatinib in newly diagnosed patients, and all clearly produced more rapid responses than imatinib at the dose levels employed.[7-9] A phase III study of ponatinib compared with imatinib is just starting, and the same may prove to be true for ponatinib. The newer TKIs are, however, generally more expensive than imatinib, and when the patents on imatinib expire and generic versions become available, the difference in cost may increase still further. The critical question is therefore: Is it reasonable to start all new CML patients on treatment with imatinib alone and continue the drug indefinitely in those who fare well, or should one start treatment with one of the newer agents or possibly with imatinib in combination with another anti-CML agent in order to secure the best possible outcome for an individual patient?

TKIs: Side-Effect Overview

TABLE 1Comparison of Efficacy, Adverse Events, and Laboratory Abnormalities Associated With the Four TKIs Used as Initial Therapy for Patients With CML-CP

Side effects differ from drug to drug, but for TKIs it is possible to define a drug class side-effect profile; this includes myelosuppression (the main side effect), fatigue, fluid retention, hepatotoxicity, gastrointestinal disturbances, myalgias, arthralgias, rashes, prolongation of the QTc interval, hypocalcemia, hypophosphatemia, and increases in amylase and lipase levels. All four TKIs can cause these effects, but their relative frequencies differ: for example, facial edema is very common with imatinib but rare with dasatinib, whereas rashes are relatively common with nilotinib but less prominent with dasatinib (Table 1)

Imatinib

Imatinib was the first TKI. Typically it is given once a day at a standardized dose of 400 mg, although the maximum tolerated dose was never formally established. Some studies have tested higher doses—eg, 600 or 800 mg daily.[10,11-13] Imatinib is normally given with food to prevent or minimize nausea.

Side effects

We have more than 14 years of experience with imatinib, and 12 years of experience with imatinib as first-line therapy for CML. The drug is safe. It has been taken by many thousands of patients, and the side-effect profile is well established. Nausea, myalgia, arthralgia, and fluid retention are seen far more frequently in patients receiving imatinib than in those treated with other TKIs. Nausea and fluid retention can be easily managed, but arthralgia and myalgia may persist as late side effects in a minority of patients despite optimal support.

Efficacy

Approximately 70% of patients who receive imatinib as first-line therapy achieve a complete cytogenetic response (CCyR) by 12 months, and 80% do so by 5 years.[5] In a series of 282 patients treated at Hammersmith Hospital in London, the 8-year probability of overall survival on an intention-to-treat basis was 84%, the 8-year probability of being alive and in CCyR was 77%, and the 8-year probability of imatinib failure–free survival was 50%,[14] indicating that although the majority of patients who begin imatinib therapy fare well, a significant proportion need a change of therapy on account of unsatisfactory response or side effects.

Attempts have been made to start treatment for CML-CP by combining imatinib with other agents, notably with interferon alfa. In two studies, this combination yielded better shortterm results than the use of imatinib alone, but there was no difference in progression-free or overall survival.[13,15] In one study, there was no demonstrable difference between the regimen that included interferon and the regimen that did not include it.[16] Thus, the suggestion that interferon together with imatinib might be the best initial therapy for CML is so far unproved.

Summary

The obvious advantages of imatinib are that it is the only drug with which we have long-term (>10 years) experience, its side-effect profile is well known, and in most countries it is the least expensive of the available TKIs. Conversely, imatinib probably induces a higher proportion of insidious low-grade side effects (eg, muscle cramps) than nilotinib or dasatinib. At a standard dosage, the proportion of patients who achieve CCyR by 1 year is lower with imatinib than with nilotinib or dasatinib.